NEW DESIGNS AND STATISTICAL METHODS FOR NIDDK STUDIES

描述(改编自申请人的摘要)：国家 糖尿病、消化和肾脏疾病研究所(NIDDK)有一个 赞助新疗法临床研究的悠久历史。这 应用为NIDDK提出新的设计和统计方法 临床研究。此应用程序的主要重点是 临床试验和剂量反应新设计的发展 哪些研究将更好地惠及参与 学习。这些新设计是响应驱动的；也就是说，响应来自 研究中之前的受试者被用来确保更高的概率 未来的受试者将被分配到治疗或剂量水平 到目前为止，“表现”得更好。响应驱动的设计具有丰富的 生物统计学研究的历史，对临床医生很有吸引力，但 由于现有统计数据的限制，不经常使用 技巧。本申请的很大一部分涉及补救措施， 将使响应驱动的设计适用于更多的I-III期临床 NIDDK感兴趣的疾病的新疗法的试验。 以前的方法论工作很少涉及反应的使用- 用于剂量反应或毒性研究的驱动设计。这个项目 提出了一类基于广义Polya的随机化设计 骨灰盒模型，允许特定分位数的目标和 防护时剂量-反应关系的描述 患者不会被分配到剧毒剂量水平。这节课 的设计本质上是非参数的，并且允许各种各样的 设计选择。这样的设计对预试阶段很有意义 明显的伦理利益的新疗法，但也是 适用于综合疗效/毒性反应，通常令人感兴趣 在第二阶段试验中。与估计和推断有关的问题和问题 在实际实施中对该设计进行了检验。比较 与其他已有的方法进行了比较，并提出了一些建议。 还提出了其他响应驱动的设计，包括完全顺序的 剂量反应研究的设计，滴定或剂量范围的设计 实验，一种适合于第三阶段临床试验的设计 多个治疗臂，以及适合生存试验的设计。 这些设计中的每一个都受到现实研究场景的激励，并且 道德利益与实际问题一起被权衡 实施；处理了潜在的批评，并努力 提出解决方案。 大多数NIDDK试验采用分组序贯监测技术。二 其他主题，关于数据的分组顺序监视的专著 临床试验，以及三个连续监测的设计 治疗臂在临床试验中采用标准随机设计时 是用的，也是开发出来的。

DESCRIPTION (adapted from the applicant's abstract): The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) has a long history of sponsoring clinical studies of new therapies. This application proposes new designs and statistical methods for NIDDK clinical studies. The primary emphasis of this application is the development of new designs for clinical trials and for dose-response studies which will better benefit the individual participant in the study. These new designs are response-driven; that is, responses from previous subjects in the study are used to ensure a higher probability that future subjects will be assigned to treatments or dose levels "performing" better thus far. Response-driven designs have a rich history in biostatistical research and are attractive to clinicians, but are not utilized very often due to limitations of existing statistical techniques. A large part of this application addresses remedies which will make response-driven designs feasible for more Phase I-III clinical trials of new therapies for diseases of interest to the NIDDK. Little previous methodological work has addressed the use of response- driven designs for dose-response or toxicity studies. This project presents a randomized class of designs based on the generalized Polya urn model which allows targeting of a particular quantile and description of the dose- responsive relationship while protecting patients from being assigned to highly toxic dose levels. This class of designs is essentially nonparametric and allows a wide variety of design choices. Such designs will be of interest for pre-testing stages of new therapies for the obvious ethical benefits, but are also applicable to combined efficacy/toxicity responses, often of interest in Phase II trials. Problems with estimation and inference and issues in the practical implementation of the design are examined. Comparison with other existing methodology is proposed. Other response-driven designs are proposed, including a fully sequential design for dose-response studies, a design for titration or dose ranging experiments, a design appropriate for Phase III clinical trials with multiple treatment arms, and a design appropriate for survival trials. Each of these designs is motivated by realistic study scenarios, and ethical benefits are weighed along with issues of practical implementation; potential criticisms are addressed, and efforts made to propose solutions. Most NIDDK trials employ group sequential monitoring techiques. Two other topics, a monograph on group sequential monitoring of data in clinical trials, and a design for sequential monitoring of three treatment arms in a clinical trial when a standard randomization design is used, are also developed.